Hydroxamic acid analogs are important targets in medicinal chemisty because of their bidentate chelating interaction with the catalytic Zn2+ in the active site of metalloproteinases. (Fingleton, B. Expert Opin. Ther. Targets (2003), 7(3), 385–397; Clendeninn, N. J.; Appelt, K., Eds. Hydroxamic acid matrix metalloproteinase inhibitors. Humana Press: Totowa, N.J., 2000; pp. 113–142.
The direct solution-phase hydroxyamination of esters is generally achieved by a two-step methods involving 1) the potassium salt of hydroxylamine followed by the addition of the ester in alcohol solvent, Hauser, C. R.; Renfrow, W. B. Org. Syn., Coll. Vol. 2 1943, 67–68, or 2) saponification of the ester followed by activation of the acid and quenching with an O-protected hydroxylamine analog, Burns, C. J. et al. Angew. Chem. Int. Ed. 1998, 37, 2848–2850; Mori, K., et al. Tetrahedron 1988, 44, 6013–6020. In special cases, the hydroxyamination of esters has been achieved via enzymatic methods Chen, S-T. et al. Bioorg. Med. Chem. Letters 1992, 2, 1685–1690, and, for more reactive esters, by treatment with excess hydroxylamine in alcohol solvent. Spengler, J., et al. Synthesis 1998, 1, 67–70.
The solid-phase synthesis of hydroxamic acids via the direct cleavage of an ester-linked substrate has been reported. Dankwardt, S. M. SYNLETT 1998, 7, 761; Dankwardt, S. M., et al. Bioorg. Med. Chem. Letters 2000, 10, 2513–2516. However, this method requires exposure of the esterified resin to concentrated aqueous hydroxylamine in THF over 2 days and is limited in scope because of irreproducibility. Zhang, W., et al. J. Comb. Chem. 2001, 3, 151–153; Thouin, E., et al. Tetrahedron Letters 2000 457–460. The issue with simply using a hydroxylamine resin is that important chemistries like the Mitsunobu reaction and alkylations are problematic because of the acidic NH group (pKa˜10).
Alternatives to address this include a method where ester libraries are made on-resin, cleaved and re-attached to a hydroxylamine resin then cleaved again, Salvino, J. M., et al. Bioorg. Med. Chem. Lett. 2000, 10, 1637–1640; and specialized resins, Barlaam, B. et al. Tetrahedron 1999, 55, 7221–7232; Mellor, S. L., et al. Tetrahedron Letters 1997, 38, 3311–3314; Floyd, C. D., et al. Tetrahedron Letters 1996, 37, 8045–8048; Ede, N. J., et al. Letters Pep. Sci. 1999, 6, 157–163; Bauer, U, et al. Tetrahedron Letters 1997, 7233–7236, where the hydroxylamine-linking group is fully protected. Ngu, K., et al. J. Org. Chem. 1997, 62, 7088–7089.
Also reported in the literature is the formation of amides from the reaction of an ester with an amine in the presence of small amounts of cyanide ion (Hogberg, T., et al. J. Org. Chem. 1987, 52, 2033–2036).